Engineering vascularized bone tissue for scaffolding repairing remains a significant clinical problem. One major challenge is to develop systematic models based on coordinated experiments. The second challenge is to understand the underlying mechanisms of the synergistic effects of the temporal combinations of growth factor cues. The third challenge in bone tissue engineering is the establishment of a well functional vascular network. In order to address these challenges, we plan to take advantage of our expertise in biomaterials, cell biology and computational modeling to develop coherent experimental protocols, material engineering and multi-scale mathematical models for systematically optimizing bone regeneration (called sBone system). This bone repairing process is likely under the control of many complex pathways. Using the classical BMP-2/IGF-1 dual-growth-factor temporal combination system as the biological model, our systems biology research, led to the hypothesis that BMP-2 induces Smad1/2 signaling pathways of MSCs, gradually remodels the expression pattern of Runx2 and Osx pathways, and thus sensitizes MSCs to the late IGF-1 cue. We will first develop in-vitro multi-temporal scale model for optimal temporal combinations of growth factors to promote bone regeneration, and conduct in-silico screening using the model and in-vitro validation of candidate growth factor combinations. Second, we will develop a predictive multi-scale model of bone regeneration within the novel pre-vascularized macro-porous, biodegradable beta-tricalcium phosphate (?-TCP) based scaffolds loaded with the programmed growth factor release system. And finally we will guide the design of the chemo-physical features of bone scaffolds by in-silico optimization of growth factor release profiles and the geometric parameters of the macro-pores. Through integration of in silico and experimental analyses, we will be able to use systems biology approaches to optimize the temporal combinations of growth factor release from the engineering vessel grafted 3D scaffolds for successful in-vivo bone regeneration.